The present invention generally relates to the field of oral prosthetics and tissue engineering. More specifically, a novel, artificial fluid secreting prosthesis for non-invasive insertion is disclosed. Further, methods of use of the foregoing are provided.
For many years, investigators have studied diseases of the mouth and mechanisms by which salivary glands produce their secretions. (Bricker et al., eds., xe2x80x9cOral Diagnosis, Oral Medicine and Treatment Planning,xe2x80x9d Lea and Febiger, Philadelphia, Pa., 1994; Baum et al., Methods Enzymol, 192:26-37 (1990); and Baum et al., Ann. NY Acad. Sci, 694:17-23 (1993)). Salivary glands have provided a valuable experimental model for generations of scientists interested in neurofunctional controls, from Claude Bernard and Ivan Pavlov to the present day. They are highly responsive epithelial tissues whose function can be readily and non-invasively measured. (Young et al., xe2x80x9cSecretion of salivary and salt glands,xe2x80x9d Membrane Transport in Biology, Vol 4, Giebisch et al., eds., Springer-Verlag, Berlin/New York, 1979:563-674; and Mandel, J. Amer. Dent. Assoc., 119:298-304 (1989)).
All salivary glands are compound tubuloalveolar glands. Small intrinsic salivary glands are scattered within the mucosa of the tongue, palate, lips, and cheeks. Saliva from these glands keeps the mouth moist at all times. Large extrinsic salivary glands secrete saliva during eating. In humans there are three extrinsic salivary glands (parotid, submandibular, and sublingual) that lie external to the mouth but are connected to the mouth through ducts. From an open mouth, the cannulation of the duct orifice, a procedure that in humans requires no anesthesia, affords direct access to the luminal membrane of virtually every cell in this secretory tissue.
Salivary glands consist almost entirely of well-differentiated epithelial cells that exist as a monolayer bordering on an extensively arborized lumen. (Cook et al., xe2x80x9cSecretion by the major salivary glands,xe2x80x9d Physiology of the Gastrointestinal Tract, Johnson, ed., Raven, New York, 1994:1061-1117). The secretory cells of these glands produce a watery secretion composed of enzymes and ions, while mucous cells produce mucous. Depending on the type of salivary gland, different amounts of secretory cells and mucous cells are present
There are many subjects who effectively have lost all functional salivary epithelium, both acinar and ductal, and experience severe salivary hypofunction. Each year in the United States alone, approximately 30,000 individuals undergo therapeutic ionizing radiation (IR) for head and neck malignancies. (Silverman, Clin. Geriatric Med., 8:529-541 (1992)). Acinar cellsxe2x80x94the fluid, salt, and protein-secretory cell type in the glandsxe2x80x94are very sensitive to radiation and are readily destroyed during radiation therapy. (Kashima et al., Am. J. Roentgenol Radium Ther. Nucl. Med., 94:271-291 (1965)). In addition to irradiated subjects, many other individuals with Primary Sjogren""s syndrome or an autoimmune exocrinopathy also exhibit salivary gland hypofunction. In consequence, individuals having hypofunctional salivary glands suffer from rampant dental caries (decay), frequent mucosal infections (such as oral Candidiasis), dysphagia (swallowing difficulties), as well as, considerable pain and discomfort.
At present, there is no conventional effective treatment of salivary gland hypofunction. While gene transfer to glandular epithelial tissue offers promise, at present, the expression of transferred genes is transient at best and many subjects lack glandular epithelial tissue for gene transfer altogether. The transplantation of mammalian salivary glands has also been tried but this option is clinically undesirable because of an insufficient donor supply, the continuous need for immunosuppression, and surgical difficulty. (Eid et al., Transplantation, 64:679-683 (1997)). In view of the foregoing, and not withstanding the various efforts exemplified in the prior art, there remains a need for an artificial fluid secreting prosthesis and a deployment methodology for oral implantation so as to treat individuals suffering from salivary gland hypofunction.
Compositions and methods based on the discovery of an artificial fluid secreting prosthesis are disclosed. In a first set of experiments, it is demonstrated that subjects having irradiated salivary gland cells can be induced to secrete fluid subsequent to transfer of a gene encoding aquaporin-1 (AQP1). In a second set of experiments, it is shown that heterologous genes transferred to salivary gland cells, such as human xcex11-antitrypsin (hxcex11AT) and human growth hormone (hGH), can be expressed in vivo and these products are detected in the blood of the recipient organism. In a third set of experiments, an artificial salivary gland is constructed. This device has a support, an attachment surface joined to the support, and joined to the attachment surface are a polarized monolayer of allogenic or autologous cells that are engineered to secrete ions and water unidirectionally.